Monitoring Method and Apparatus

ABSTRACT

A device for remote management of patients suffering from heart failure and hypertension can measure one or more biomarker. The device aids in monitoring the efficacy and safety of treatment in such patients.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.13/302,020, filed Nov. 22, 2011, now, U.S. Pat. No. 8,361,389, which isa continuation of U.S. patent application Ser. No. 11/013,353, filed onDec. 17, 2004, now, U.S. Pat. No. 8,129,191, which claims priority toU.S. Patent Application No. 60/620,968, filed on Oct. 22, 2004, and toU.K. provisional application No. 0329288.5, filed Dec. 18, 2003, each ofwhich is incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to a method and apparatus for monitoring apatient.

BACKGROUND

Heart failure is a chronic, progressive disease that affects 1.5-2% ofthe general population of the Western world. The prevalence andincidence of heart failure is growing due to an aging population and agreater number patients who survive a myocardial infarction.

Clinically, heart failure is characterized by a syndrome ofbreathlessness and fatigue, often accompanied by fluid retention, asindicated by an elevated jugular venous pressure and edema. Theprogression of heart failure is defined in four stages. The term heartfailure refers to all of these.

Stage A—at risk: patients at high-risk of developing heart failure(patients with coronary heart disease, diabetes, hypertension, and/orvalvular heart disease).

Stage B—pre-heart failure: patients with structural heart disease butwithout clinical heart failure symptoms, many of whom have decreasedsystolic function.

Stage C—heart failure: patients who have prior or current symptomaticheart failure due to systolic or diastolic dysfunction and who areresponding to therapy.

Stage D—advanced heart failure: patients in end-stage orrefractory-to-therapy.

Many of the tests and procedures for accurately and successfullydiagnosing, managing and treating heart failure are complex, expensiveand available only at a hospital or other health-care setting. Methodsfor patients to manage heart failure at home or otherwise outside ahealth-care setting are less successful.

SUMMARY

A patient with pre-heart failure or heart failure can be managed in thehome or a non-hospital setting. To help the patient manage heartfailure, a means is provided to detect or monitor the patient'scondition. The device can detect or monitor, for example, onset of acutedecompensation, episodes of acute decompensation, episodes of hypoxia,episodes of myocardial ischemia, episodes of myocardial apoptosis orinfarction, response to diuretic therapy, response to fluid intake,response to sodium intake, response to primary pharmacological agents(e.g., ACE inhibitor, β-blocker, aldosterone II receptor antagonist),and response to secondary pharmacological agents (e.g.,hydralazine/isosorbide dinitrate). A patient in the pre-heart failurestage is often characterized with the presence of hypertension.Hypertension presents many of the same symptoms and in many instances istreated in the same manner as heart failure. Therefore, the methods anddevices are also applicable to hypertensive patients. The device is alsouseful for patients at risk of a myocardial infarction, for example, apatient who has survived a first myocardial infarction and is at riskfor future myocardial infarction.

A device allows the patient to perform frequent measurements of one ormore biomarkers, collect information on signs and symptoms by paperchart or electronic diary, and, if necessary, to compute the measurementof biomarker(s) with other parameters such as signs and symptoms (e.g.breathlessness, cough, edema, decreased exercise tolerance, unexplainedconfusion or altered mental state, weight gain, fatigue, abdominalsymptoms or signs related to ascites and hepatic engorgement, bloodpressure, heart rate, variability of heart rate, and oxygen saturation).The biomarkers measured by the device can include, but are not limitedto, markers of myocardial stretch, myocardial apoptosis or injury,myocardial ischemia, anemia, renal function, electrolytes, and markersof sodium balance. Because the test is simple enough to be carried outin the patient's home, daily measurements can be obtained and allow foran earlier notification of a detrimental change in the patient'scondition than would otherwise be possible. Thus, the patient or ahealthcare professional is able to review real-time data on thepatient's pathophysiological state and response to therapy.

In one aspect, the present invention provides a means to determine thepathophysiological status and therapeutic response of a mammaliansubject, comprising: a detector for measuring, in a sample taken fromthe subject, the level of a marker of:

left ventricular volume overload or myocardial stretch, renal function,myocardial apoptosis or injury, myocardial ischemia, electrolytebalance, sodium retention or inflammation.

The detector can be associated with a device for providing a display ofthe result of the measured parameters, and a means to manually orautomatically input data from other measurements or observations or riskfactors. The other measurements, observations or risk factors canincluding breathlessness, cough, edema, decreased exercise tolerance,unexplained confusion or altered mental state, weight gain, fatigue,abdominal symptoms or signs related to ascites and hepatic engorgement,blood pressure, heart rate, heart rate variability, oxygen saturation,age, gender, body mass index, frequency and volume on urination, drycough, dry mouth, nausea, pain, fluid intake, salt intake, drugadministration, exercise, weight control, and assessment of quality oflife.

In another aspect, the present invention provides a means to input aseries of preset or predetermined levels (decision points) for eachparameter (e.g. a baseline level and a single or multiple actionlevels).

A baseline level for a marker may be assigned when the patient isstabilized. The baseline level can be a normal or target level. Relativechanges with respect to the baseline value will then reflectimprovements or deterioration in the patient's status allowingintervention by the patient or healthcare provider if necessary.

An action level for a marker is a level sufficiently separated from thebaseline level to indicate a change in the patient's condition. Thiswould result in the patient and, if necessary, the healthcareprofessional being alerted to a change in status. If appropriate, arecommended course of action can be relayed via the display or anothermeans of communication. Relative changes relative to the action levelwould indicate improvements or further deterioration in the patient'scondition.

The absolute level, or the rate of change, or the magnitude of change inthe measured parameter can be compared to a predetermined level, such asa previously stored measurement or a preset action level.

The result of a measurement can be stored. The measurement can includeraw data or interpreted data, such as absolute biomarker concentration,biomarker level relative to a preset action level, rate of change of thebiomarker, magnitude of change of the biomarker, or any manually orautomatically entered parameter.

The outcome of any measured or interpreted parameter or any manually orautomatically entered parameter can be compared to the result for anyother parameter.

The device can display and store in memory the findings of any of theabove outcomes.

The device can relay stored data to a healthcare professional or othercaregiver.

The device can be configured to determine when the user should perform atest or evaluate any other parameter.

The device can be configured to determine whether the user performed atest, administered a drug or any other intervention, or evaluated anyother parameter.

The device can upload data from the instrument or to download data tothe instrument.

In one aspect, a device for monitoring cardiac health includes adetector configured to measure, in a sample taken from a patient, alevel of a biomarker selected from the group consisting of: a marker ofleft ventricular volume overload or myocardial stretch, a marker ofmyocardial apoptosis or injury, a marker of myocardial ischemia, amarker of inflammation, a marker of anemia, a marker of renal function,a marker of electrolyte balance, and a marker of sodium retention.

The device can be configured to provide an output to the patient. Thedetector can be configured to measure a level of a second biomarker. Thesecond biomarker can be a marker of left ventricular volume overload ormyocardial stretch, a marker of myocardial apoptosis or injury, a markerof myocardial ischemia, a marker of inflammation, a marker of anemia, amarker of renal function, a marker of electrolyte balance, or a markerof sodium retention. When the first biomarker is a marker of leftventricular volume overload or myocardial stretch and includes anatriuretic peptide, the second biomarker can be a marker of renalfunction.

The marker of left ventricular volume overload or myocardial stretch caninclude a natriuretic peptide. The marker of myocardial apoptosis orinjury can include a troponin, urotensin, or a urotensin-relatedpeptide. The marker of myocardial ischemia can include ischemia-modifiedalbumin, oxygen-regulated peptide (ORP150), free fatty acid, Nourin-1,urotensin, or a urotensin-related peptide. The marker of inflammationcan include E-selectin, P-selectin, intracellular adhesion molecule-1,vascular cell adhesion molecule-1, Nourin-1, interleukin-1β,interleukin-6, interleukin-8, interleukin-10, tumor necrosisfactor-alpha, hs-CRP, neutrophils, or white blood cell count. The markerof anemia can include hemoglobin or hematocrit. The marker of renalfunction can include creatinine or Cystatin C. The marker of electrolytebalance can include Na⁺ or K⁺. The marker of sodium retention caninclude uroguanylin.

In certain circumstances, the first biomarker can be a marker of leftventricular volume overload or myocardial stretch, and the secondbiomarker can be a marker of renal function.

The device can include a probe for measuring a vital sign of thepatient. The probe can measure a weight, a heart rate, variability ofheart rate, a breathing rate, a blood pressure, a temperature, a bloodoxygen saturation, or an electrocardiogram of the patient.

The device can include a memory capable of storing the results of ameasurement of the level of the biomarker. The device can be configuredto compare the result of a measurement of the level of the biomarker toa stored result. The memory is can store a threshold value of the levelof the biomarker. The device can be configured to compare the result ofa measurement of the level of the biomarker to the threshold value. Thedevice can instruct or indicate to the patient or healthcareprofessional for the patient to commence, cease or alter a treatmentplan when the measurement exceeds an upper or lower threshold value, orwhen the rate of change in the level of the biomarker between two ormore measurements exceeds an upper or lower value. The treatment plancan include use of a diuretic. The device can further instruct thepatient to obtain a measurement of a marker of renal function. Theinstruction can be made visually, on a display, printed or recoded on anoutput medium, or indicated by a sound or combination of sounds. Anupper threshold is exceeded when the level of the biomarker is greaterthan the threshold value; and a lower threshold is exceeded when thelevel of the biomarker is less than the threshold value.

The device can include a display for displaying the results of themeasurement, a patient query, or a patient instruction. The device caninclude an input device for supplying a response to a patient query. Thedevice can be configured to provide a patient instruction in response tothe results of the measurement. The instruction can be personalized.

In another aspect, a method of monitoring a patient includes measuringin a sample taken from a patient, a level of a biomarker selected fromthe group consisting of: a marker of left ventricular volume overload ormyocardial stretch, a marker of myocardial apoptosis or injury, a markerof myocardial ischemia, a marker of inflammation, a marker of anemia, amarker of renal function, a marker of electrolyte balance, and a markerof sodium retention.

The method can include providing an output to the patient. The methodcan include measuring in a sample taken from a patient, a level of asecond biomarker selected from the group consisting of: a marker of leftventricular volume overload or myocardial stretch, a marker ofmyocardial apoptosis or injury, a marker of myocardial ischemia, amarker of inflammation, a marker of anemia, a marker of renal function,a marker of electrolyte balance, and a marker of sodium retention.

The method can include recording the measured level of the biomarker.The method can include measuring the level of the biomarker at a latertime, and comparing the recorded measured level to the later measuredlevel. The method can include determining whether the patient issuffering from one or more symptoms associated with heart failure. Themethod can include measuring a weight, a heart rate, variability ofheart rate, a breathing rate, a blood pressure, a temperature, a bloodoxygen saturation, or an electrocardiogram of the patient.

In another aspect, a method of monitoring a patient includes making asingle measurement or series of measurements of the level of a firstbiomarker of left ventricular volume overload or myocardial stretch; andproviding, depending upon the levels of the first biomarker, anindication or instruction to the individual or healthcare professionalto commence, cease or alter a diuretic treatment program. The method mayalso indicate to the user (e.g., patient or healthcare professional) tomeasure a level of a marker of renal function. Depending upon theresults of the measurement of the level of the first biomarker and/or ofthe level of the marker of renal function, the method may also provide afurther indication to alter the diuretic treatment plan. Altering theplan can include continuing or stopping the diuretic treatment program,increasing or decreasing the length or levels of the diuretic treatmentprogram, and/or to commencing a diuretic treatment program using afurther diuretic having a different potency. Thus the individual orhealthcare professional can control the level of the first biomarkerover time. Measurement of a marker of renal function provides anindication of the degree or extent of hydration of the individual,ensuring that the individual does not become too dehydrated as aconsequence of taking a diuretic. An indication to commence a diuretictreatment program may be given when the level of the first biomarkerexceeds a certain upper threshold or rate of change. Similarly, when thelevels of the first biomarker fall below a certain lower threshold orrate of change, an indication may be given to stop or change thediuretic treatment program. The individual may then continue to monitorthe levels of the said first biomarker to ensure that they remain withinthe upper and lower thresholds. Should the level of the first biomarkerstart to increase, the method may provide an indication to recommencediuretic therapy and monitoring for a marker of renal function. Theabsolute values of upper and lower thresholds and rates of change may befixed or may vary depending upon the individual concerned. A device anda kit suitable for carrying out the above method are also provided.

In another aspect, a health care kit includes a test cartridge includinga sample port and a first assay, wherein the first assay recognizes amarker of left ventricular volume overload or myocardial stretch, amarker of myocardial apoptosis or injury, a marker of myocardialischemia, a marker of inflammation, a marker of anemia, a marker ofrenal function, a marker of electrolyte balance, or a marker of sodiumretention, and a device including a detector configured to measure alevel of the biomarker recognized by the assay. The first assay caninclude an antibody that recognizes a marker of left ventricular volumeoverload or myocardial stretch, a marker of myocardial apoptosis orinjury, a marker of myocardial ischemia, a marker of inflammation, amarker of anemia, or a marker of sodium retention.

The kit can include a second test cartridge including a sample port anda second assay, wherein the second assay recognizes a marker of leftventricular volume overload or myocardial stretch, a marker ofmyocardial apoptosis or injury, a marker of myocardial ischemia, amarker of inflammation, a marker of anemia, a marker of renal function,a marker of electrolyte balance, or a marker of sodium retention. Thesecond assay can include an antibody that recognizes a marker of leftventricular volume overload or myocardial stretch, a marker ofmyocardial apoptosis or injury, a marker of inflammation, a marker ofmyocardial ischemia, a marker of anemia, or a marker of sodiumretention.

The first assay can include an antibody that recognizes a natriureticpeptide. The second assay can recognize a marker of renal function.

The details of one or more embodiments are set forth in the drawings anddescription below. Other features, objects, and advantages will beapparent from the description, the drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is diagram illustrating a diagnostic device and an associatedtesting cartridge.

DETAILED DESCRIPTION

In a patient with heart failure, cardiac output is inadequate to meetthe metabolic needs of the body, either at rest or with exercise. Anincrease in cardiac filling pressure or volume usually occurs as well.Heart failure is most commonly due to left ventricular systolicdysfunction (LVSD) where the myocardium fails to contract normally andthe left ventricle is usually dilated. As the disease progresses, thebody responds to the diminished cardiac output through activation of therenin-angiotensin-system (RAS) causing arterial vasoconstriction,enhanced sodium reabsorption, and volume expansion. There is an increasein presynaptic stimulation of sympathetic nerves to enhancenorepinephrine release, which is deleterious in the long-term for thepatient. These effects, which are mediated by angiotensin II binding tothe AT₁ receptor, are immediate and are compensatory changes thatdevelop to augment cardiac output and increase perfusion pressure tovital organs. In addition to these immediate hemodynamic effects,angiotensin II also causes cardiac remodeling through fibroblast andmyocyte proliferation. Remodeling involves increases in left ventriclevolume and mass, as well as changes in conformation that ultimately leadto diastolic and systolic dysfunction. Another immediate effect ofangiotensin II relevant to the heart failure patient is an increasedthirst caused by the release of arginine vasopres sin which canexacerbate the fluid retention.

The overall treatment plan for a patient with hypertension, pre-heartfailure (Stage B) or heart failure (Stages C or D) includes carefulmanagement of pharmacological therapy, diet and lifestyle. The primarygoals are prolongation of the patient's life by preventing, slowing,halting, or reversing the progressive condition, relief of the patient'ssymptoms, and improvement in the patient's quality of life.

Hypertension is defined by the National Heart Lung and Blood Instituteas systolic blood pressure of 140 mm Hg or greater, or diastolic bloodpressure of 90 mm Hg or greater. Current treatments are very effectivein improving cardiovascular health to decrease the incidence andseverity of hypertension complications. However, only about one quarterof hypertensive patients adequately control their disease. Chronichypertension is a “silent killer” with no symptoms to remind of the needfor continuous treatment. Compliant hypertension therapy with favorableoutcomes depends on strong initial education backed by ongoingreinforcement of treatment benefits. Unfortunately, the widespread useof arterial blood pressure measurement in these patients is known to bea poor predictor of mortality. The ideal measurement is left ventricularfilling pressure because this elevated pressure is part of the processthat leads to left ventricular hypertrophy and eventually heart failure.However, such a measurement is not routinely practical. An alternativeapproach would be to measure a marker of left ventricular volumeoverload to give an indication of increased ventricular pressure.

Symptoms and signs of heart failure and a worsening condition includebreathlessness, cough, edema in the lower extremities, decreasedexercise tolerance, unexplained confusion or altered mental state,weight gain, fatigue, and abdominal symptoms or signs related to ascitesand hepatic engorgement.

Important classes of drugs used in the treatment of heart failureinclude ACE inhibitors, beta-blockers, aldosterone receptor blockers,and diuretics. ACE inhibitors, beta-blockers, and aldosterone receptorblockers reduce morbidity/mortality whereas diuretics improve thepatient's quality of life (primarily by reducing symptoms). Thepatient's lifestyle can have a major influence on the efficacy of thedrug regimen through poor compliance with drug administration and poordiet. For example, fluid overload can blunt the therapeutic effects andfluid depletion can exacerbate the adverse effects of other drugs. Bothsituations can lead to dangerous outcomes.

The stages of the treatment plan include therapy optimization andmaintenance. In the optimization stage the patient should first bestabilized if there is evidence of fluid overload and then appropriateadditional pharmacotherapy should be introduced.

A patient's control of fluid balance can be achieved with use of adiuretic and, if necessary, restriction of salt and fluid intake.Diuretics need to be monitored to track electrolyte disturbances,dehydration, and excessive water retention. Inappropriate management ofdiuretics has a negative impact on the effectiveness of concomitant drugtherapies. Diuretic therapy can be self-managed by the patient. Thepatient monitors his or her weight daily and if significant weight gainoccurs over a period of a few days then the patient can double thediuretic dose (e.g., increase Furosemide from 40 mg bid to 80 mg bid)and, if necessary, add a second diuretic (e.g., Metolazone) for a shorttime until the normal dry weight is resumed. This strategy should beused whenever the patient experiences weight gain of 3 pounds in 2 days,or five pounds in one week.

When the patient is euvolemic, angiotensin II activity should be reducedby inhibiting the action of ACE on angiotensin I using an ACE inhibitor.Alternatively, the binding of angiotensin II to its AT₁ receptor can beblocked using an angiotensin receptor blocker (ARB). ACE inhibitors areusually started at a low dose and then up-titrated over 2-3 weekintervals as tolerated either symptomatically or hemodynamically.Careful attention to tolerance is monitored by laboratory parameters(e.g., serum creatinine and serum electrolytes), blood pressure, andsymptomatic side-effects (e.g., development of a dry cough).

β-blockers are widely used as an additional component of the treatmentplan to prevent norepinephrine-mediated effects. Norepinephrine is toxicto cardiac cells, stimulates apoptosis, and has a negative effect oncardiac structure by stimulating myocyte hypertrophy and fibroblastproduction, part of the remodeling process. β-blockers should beinitiated cautiously in certain patients. Assessment of tolerance isusually through measurement of heart rate and blood pressure.

As described above, effective pharmacological treatments exist that canslow progression of the disease and extend the patient's life. However,these drugs are rarely used at their therapeutic levels becausephysicians have no easily accessible method to demonstrate effectivenessof increased doses of the drug. Instead, side effects (which aremanageable by careful adjustment in other medications, such as diureticdose) often result in drugs being used at sub-optimal levels. Further,patients often have poor compliance with their drug therapy. Even forthose patients who are able to self-manage their diuretic therapy,weight tracking is an insensitive indicator of increasing volumeoverload.

Poor compliance by the patient to diet (fluid intake and salt intake)and drug treatment is the main reason for episodes of acutedecompensation, independent of whether the patient is receivingappropriate pharmacological therapy. During fluid retention, plasmavolume can increase by as much as 70% during an episode ofdecompensation. Such life-threatening events require hospitalization andaggressive management. Detecting an impending event (such as bymeasuring a change in a biomarker) would allow avoidance of dangerousevents by careful adjustment of diuretics and diet.

In the event of fluid retention, fluid overload will cause leftventricular volume overload, putting strain on the heart. Ultimately,cardiac output is reduced, causing fluid build-up in the lungs resultingin pulmonary congestion. On the other hand, in the event of fluiddepletion, the condition of dehydration will arise. In either case, afurther consequence can be an unfavorable change to the levels ofelectrolytes.

Ideally, the health care provider has information on left ventricularvolume overload, fluid retention, fluid depletion, electrolyte balance,and renal function. Information on signs and symptoms will also help thecaregiver manage the patient's treatment.

Measurement of left ventricular volume overload can be obtained usinghospital-based technologies, such as chest X-ray, electrocardiography,echocardiography, radionuclide imaging and dilutional analysis. A chestX-ray will reveal cardiomegaly, venous congestion, and chamberenlargement.

Electrocardiography will reveal ventricular hypertrophy, and atrialenlargement. Echocardiography is used to determine systolic anddiastolic left ventricular performance, chamber size and shape, wallthickness, ejection fraction (cardiac output), and pulmonary artery andventricular filling pressures. Radionuclide scans provide more precisemeasurement of ejection fraction but require venous injection ofradioactive material. Fluid retention can be evaluated using dilutionalanalysis: the patient is injected with a tracer molecule and theresultant dilution of the tracer in the patient's blood provides anestimate of plasma volume.

Obtaining these types of measurements requires access to costlyequipment, expert knowledge, and for the patient, a visit to thehospital or clinic. Performing regular visits for serial assessment ofthe patient's condition is therefore impractical due to limitations suchas patient access, long waiting lists, and high cost.

Further, these measurements provide information only on the underlyingmacro-physiology but no specific information on what is happening at thecellular level with respect to neurohormonal control, sympatheticneurotransmitter control, and the process of cardiac remodeling.

Outside the use of aforementioned physical measurements carried out inhospital or clinic, a patient's condition can be assessed according tothe New York Heart Association four-stage classification where thepatient's functional capacity is categorized as follows:

-   -   Class I: Patients exhibit symptoms only at exertion levels.    -   Class II: Patients exhibit symptoms with ordinary exertion.    -   Class III: Patients exhibit symptoms with minimal exertion.    -   Class IV: Patients exhibit symptoms at rest.

However, there is only a weak correlation between signs and symptoms(e.g. shortness of breath, non-specific fatigue and edema) and severityof the underlying left ventricular dysfunction. Therefore, thecardiologist relies on infrequent physical measurements often onlyperformed at the time of hospital presentation or during a hospitalstay. The generalist physician and healthcare team who deliver routinecare to the patient have access to less information on which to makeclinical decisions on patient care.

The measurement of blood chemistries (for example, electrolytes,creatinine, hemoglobin, and blood urea nitrogen) is a standard componentof the patient's care plan. These are laboratory tests that require ablood specimen to be drawn at the point of care (i.e., in thephysician's office, the heart failure clinic, or the hospital).Consequently, laboratory tests are performed relatively infrequently(e.g., every 3 months during a scheduled visit or when the patient isbeing assessed because of a deteriorating condition). Therefore, theselaboratory tests do not predict or detect changes in the patient'scondition rapidly enough to prevent an adverse event, such as acutedecompensation. Nor are they performed often enough to enable optimaldrug titration.

A consequence of sub-optimal control of the patient's condition is ahigh incidence of hospital admission and readmission, most often as aresult of fluid retention leading to left ventricular volume overload.

The main causes of fluid retention are poor dietary control(uncontrolled salt and fluid intake), use of sub-optimal doses ofmedications, and poor compliance with the treatment regimen. Thesequence of events that result in hospitalization often occurs in thehome, outside the care setting, away from sophisticated technologies(e.g., echocardiography), laboratory tests, and the expert eye of thecaregiver.

The patient is encouraged to take on some responsibility for monitoringhis or her condition at home by complying with the treatment plan andchecking for signs of left ventricular volume overload. Doing so canreduce the occurrence of events that might result in hospitalization.The only current objective measurements that have been evaluated for usein the patient's home are daily weights, heart rate, and oxygensaturation.

To perform daily weights, the patient is instructed to weigh him/herselfevery morning, before breakfast, before taking any medications orliquids, after urinating, wearing the same type of clothes, withoutshoes, on the same scale (in the same location each day on a flat, hardsurface). Daily weight is recorded in a notebook and, if there has beena gain in weight of 3 pounds in 2 days, or 5 pounds in one week, thepatient is instructed to inform his or her healthcare team.

Alere Medical Incorporated (of Reno, Nev., USA) developed the Alere®Heart Monitoring Program featuring the DayLink® monitor. The AlereDayLink® monitor is a biometric measurement device with an interactivedisplay and communications appliance. The DayLink monitor gathers thepatient's weight and heart failure symptoms. To use the DayLink®monitor, a patient just steps onto the platform. Once a patient's weighthas been captured, the DayLink® monitor asks physician-specifiedquestions about the patient's symptoms, via audible voice and visualdisplay. The patient answers the questions by pressing YES or NO keys.

A major disadvantage of this approach is the insensitivity of weightmeasurement. In controlled clinical studies, daily weights have beenshown to be reasonably effective at identifying fluid overload andhelping the patient remain compliant with his or her treatment plan. Inpractice, however, daily weights are either not utilized or are tooinaccurate to be useful. For example, by the time that a significantchange in weight has been detected, the patient may already be in needof hospitalization.

Patients with heart failure suffer from a high probability of hypoxia,myocardial ischemia, and myocardial infarcts. There is currently nomeans to track the occurrence of these events in a patient's home.Failure to detect these events at an early stage results in the onset ofdeleterious consequences, worsened prognosis, and increased resourceutilization.

Consequently, the quality of care available to heart failure patientsand their resultant prognosis is lower than would be possible if moreobjective and predictive measurements were available in the home orremote care-setting to steer the treatment plan.

Markers of Left Ventricular Volume Overload and Myocardial Stretch

Measurement of neurohormones has been explored by the research communityfor several decades. Biomarkers that have been investigated include thenatriuretic peptides, A-type-(ANP), B-type-(BNP), and C-type-(CNP)natriuretic peptide and their N-terminal prohormones (N-ANP, N-BNP, andN-CNP). ANP (also known as atrial natriuretic peptide) and its inactiveform, N-ANP, have been described in, for example, Hall, Eur J HeartFail, 2001, 3:395-397, which is incorporated by reference in itsentirety.

BNP (the active peptide) and N-BNP (the inactive peptide) are found inthe circulation. Both peptides are derived from the intact precursor,proBNP, which is released from cardiac myocytes in the left ventricle.Increased production of BNP (or N-BNP; the abbreviation BNP refers toeither form of the B-type natriuretic peptide throughout this document)is triggered by myocardial stretch, myocardial tension, and myocardialinjury. Studies have demonstrated a positive correlation betweencirculating levels of BNP, left ventricular volume overload (e.g., leftventricular end diastolic pressure), and an inverse correlation to leftventricular function (e.g., left ventricular ejection fraction and leftventricular mass index).

Measurement of natriuretic peptides, in particular BNP, has been mainlylimited to diagnosis of acute decompensation in suspected heart failurepatients in the Emergency Department in a hospital setting, providing aprognosis for patients with acute decompensation during hospitalization,and therapy tracking of patients with acute decompensation prior todischarge from hospital. More recent work has investigated the role ofBNP during clinic visits and demonstrated that BNP correlates withimprovement in the patient's functional status. See, for example, KohnoM; Am J Med. 1995 March; 98(3):257-65, which is incorporated byreference in its entirety. However, testing was infrequent—tests wereconducted at baseline, 6 months, and 12 months. Similarly, the study byKawai (Kawai K; Am Heart J. 2001 June; 141(6):925-32, which isincorporated by reference in its entirety) was limited to testingintervals at baseline, 2 months, and 6 months. Studies by Troughton,Latini and McKelvie also used a testing interval of 4 months or greater(see Lancet 2000, 355:1126-30; Circulation 2002 Nov. 5; 106(19):2454-8;and Circulation 1999 Sep. 7; 100(10):1056-64, respectively, each ofwhich is incorporated by reference in its entirety).

The shortest testing interval was used by Murdoch (Murdoch D R; Am HeartJ. 1999 December; 138(6 Pt 1):1126-32, which is incorporated byreference in its entirety). Murdoch used a testing interval of every twoweeks, but the study did not consider event detection, safe titration oftherapy (by using a GFR marker; see below) or an out-patient or homecaresetting.

The only study to have used a higher testing frequency (Braunschweig, F;J Cardiovasc Electrophysiol. 2002 January; 13(1 Suppl):S68-72, which isincorporated by reference in its entirety) investigated the correlationof BNP to weight gain and hemodynamics. A major limitation of this studywas the long testing interval of weekly blood draws and again thefailure to consider the use of BNP and a GFR marker in a home caresetting—in fact, the purpose of the study was to evaluate an implantedhemodynamic sensor and compare this to weight tracking.

There is a danger that the patient or caregiver will drive the patientto a state of under-hydration if they rely on BNP levels alone.Furthermore, a target BNP level for one patient might be unsuitable foranother patient because of factors such as age, gender, body mass index,extent of hypertrophy, etc.

In the studies discussed above, the patient and their caregiver did nothave access to objective data at a suitable testing interval to allowthe prevention of future events (e.g. acute decompensation), rapid drugoptimization (e.g. ACE inhibitors, β-blockers, aldosterone receptorblocker), and controlled dose adjustment of diuretics without puttingthe patient at risk.

Markers of Myocardial Apoptosis or Injury

Markers of myocardial apoptosis provide information on cardiacremodeling, which is an effect of left ventricular volume overload.Measurement of increased myocyte apoptosis arising from excessivemyocardial stretch, norepinephrine toxicity, and other proposedmechanisms provide information on cardiac remodeling. Suitable markersinclude cardiac troponins, including the isoforms troponin I andtroponin T (TnI and TnT, respectively), as well as urotensin in all itsforms and urotensin-related peptides. Measurement of troponin hastraditionally been used to provide a diagnosis of myocardial injury orinfarction, distinct from the process of apoptosis. A sensitiveimmunoassay for a troponin isoform can allow a healthcare provider toobtain information on the extent of myocyte apoptosis and myocyte damageinduced by the aforementioned mechanisms or consistent with myocardialischemia and infarction.

Cardiac troponin levels are frequently above normal values in severaldisease states in which myocardial necrosis is not a prominent aspect,particularly in pulmonary embolism, heart failure, liver cirrhosis,septic shock, renal failure and arterial hypertension. Sub-clinicalmyocardial necrosis and increased myocardial apoptosis has beenpostulated to be the cause of the phenomenon. Increased troponin levelsmay be the result of ventricular dilatation or hypertrophy. Troponin mayact as a marker of myocardial strain, injury, and increased apoptosis(e.g., during acute decompensation or chronic worsening pre-heartfailure, heart failure, and hypertension). Apoptosis contributes tomyocardiocyte loss in cardiac disease and may have a pathophysiologicrole in left ventricular (LV) remodeling. Heart failure is associatedwith an increase in apoptosis rate and is significantly correlated withparameters of progressive left ventricle remodeling. Low levels oftroponin in the circulation correlate with apoptosis rate.

Elevated levels of troponin without elevated levels of creatine kinaseis thought to be due to release of troponin from myocardial cellswithout the disruption of myocardial cell plasma membrane.

Chen measured troponin in the plasma of patients with heart failure. SeeChen Y N, Ann Clin Biochem. 1999 July; 36 (Pt 4):433-7, which isincorporated by reference in its entirety. Elevated plasma troponinconcentrations were found in 89% of heart failure patients while plasmacreatine kinase-MB (CK-MB) showed no significant difference. Duringfollow-up, serial measurements of cardiac TnI and CK-MB were performed.In heart failure patients, improvement of the clinical profile wasassociated with declining troponin concentrations, while deteriorationof heart function was closely related to increasing troponinconcentrations. Cardiac damage relates to functionally overloadedmyocytes and troponin may be a sensitive marker both for early detectionof myocyte damage and for monitoring of function and prognosis inpatients with heart failure. Chen demonstrated that plasma troponinlevels that returned to normal in patients whose heart failure wassuccessfully treated had better outcomes than in patients whose troponinremained elevated.

Horwich demonstrated that troponin is elevated in severe heart failureand may predict adverse outcomes (Horwich, T B; Circulation. 2003 Aug.19; 108(7):833-8, which is incorporated by reference in its entirety).They presented data on 238 patients with advanced heart failure who hadtroponin assay drawn at the time of initial presentation. Patients withacute myocardial infarction or myocarditis were excluded from analysis.Troponin was detectable (greater than or equal to 0.04 ng/mL) in serumof 117 patients (49.1%). Patients with detectable troponin levels hadsignificantly higher BNP levels and more impaired hemodynamic profiles,including higher pulmonary wedge pressures and lower cardiac indexes. Asignificant correlation was found between detectable troponin andprogressive decline in ejection fraction over time.

Detectable troponin was associated with increased mortality risk.Troponin used in conjunction with BNP improved prognostic value.Therefore, troponin is associated with impaired hemodynamics, elevatedBNP levels, and progressive left ventricular dysfunction in patientswith heart failure.

Monitoring troponin to detect myocardial infarction in the context ofischemia is already accepted practice (see, for example, Apple F S,European Society of Cardiology and American College of Cardiologyguidelines for redefinition of myocardial infarction: how to useexisting assays clinically and for clinical trials; Am Heart J. 2002December; 144(6):981-6, which is incorporated by reference in itsentirety).

Therefore, routine measurement of troponin is valuable in the managementof the heart failure patient. Serial tracking of troponin will enableinformation on the patient's condition (whether stable, worsening, orimproving) to be determined and will also provide information on futureprognosis.

Markers of Inflammation

Inflammation markers can provide information about a patient'scondition. A marker of inflammation can be used to predict suddenunexpected death. The marker can be non-specific (i.e., a marker ofgeneral inflammation), or specific (i.e., a marker indicating cardiac orvascular inflammation). The marker can be a soluble adhesion molecule(e.g., E-selectin, P-selectin, intracellular adhesion molecule-1, orvascular cell adhesion molecule-1), Nourin-1, a cytokine (e.g.,interleukin-1β, -6, -8, and -10 or tumor necrosis factor-alpha), anacute-phase reactants (e.g., hs-CRP), neutrophils, and white blood cellcount.

Markers of Anemia

Markers of anemia can also be valuable in tracking heart failurepatients. According to one study, heart failure patients with lowhematocrits had a significantly higher risk of mortality than those withhematocrit >42% (see Kosiborod, M., et al. Am. J. Med. 2003, 114:112-119, which is incorporated by reference in its entirety). Forexample, a hemoglobin level or hematocrit measurement can be used as amarker of anemia.

Markers of Myocardial Ischemia

Markers of myocardial ischemia provide independent information oncardiac output, thrombus formation and embolization, and vascular bloodflow. Measurement of such markers (e.g., ischemia-modified albumin,oxygen-regulated peptide (ORP150), free fatty acid, Nourin-1, urotensinin all its forms and urotensin-related peptides, and other knownmarkers) provide an indication of onset of ischemia, magnitude ofischemia, and natural or induced reperfusion.

Markers of Renal Function

The easiest way to measure the glomerular filtration rate (GFR) is withcreatinine (Robertshaw M, Lai K N, Swaminathan R. Br J Clin Pharmacol1989; 28:275-280, which is incorporated by reference in its entirety).The rate of creatinine addition to the body is proportional to bodymuscle mass. The rate of creatinine removal is proportional to theconcentration in the plasma and the rate of glomerular filtration. Forexample, a decrease of GFR from 120 mL/min to 60 mL/min would increasethe plasma creatinine from 1.0 mg/dL to 2.0 mg/dL. Thus, changes in GFRare mirrored by reciprocal changes in the serum creatinine. Becauseserum creatinine multiplied by GFR equals the rate of creatinineproduction, a decrease in the GFR by 50% will cause the serum creatinineto increase by a factor of two at steady-state. Using only a serum orplasma creatinine measurement, the GFR, in mL/min, can be estimatedusing the formula: GFR=(140−age)×weight (kg)/0.825×plasma creatinine(μmmol/L).

Markers of renal function should be monitored regularly in patients onACE inhibitors, angiotensin II receptor inhibitors, and diuretics. Alimited elevation in creatinine level (30 percent or less abovebaseline) was seen following initiation of therapy with an ACE inhibitoror angiotensin II receptor inhibitors. The increase usually occurredwithin two weeks of therapy. Regardless of the creatinine value,manifestations of renal failure were not apparent until the GFR was wellbelow 30 mL per minute. Patients with the greatest degree of renalinsufficiency experienced the greatest protection from renal diseaseprogression. Hence, upon initiation of an ACE inhibitor or angiotensinII receptor inhibitor, GFR should be monitored, but a decrease is not areason to withdraw therapy.

The study by Lee (Lee S W; Am J Kidney Dis. 2003 June; 41(6):1257-66,which is incorporated by reference in its entirety) revealed that BNPlevels are insensitive to under-hydration in patients on hemodialysis.Lee was evaluating whether BNP might be used to assess hydration statusin a patient undergoing aggressive hemodialysis. When these findings areapplied to the process of diuresis using either intravenous or oraldiuretic therapy, one would realize that BNP cannot be used to detect astate of over-diuresis which could be life threatening. Consequently,routine measurement of a glomerular filtration rate marker is necessaryto determine whether the patient is at risk of under-hydration throughover-use of diuretic therapy.

Several biochemical methods exist for the measurement of GFR. Generally,these measure the level of an analyte that is metabolized at a constantrate, so that an increase in circulating levels of the analyte indicatesrenal failure. Suitable such analytes include creatinine and Cystatin C.See, for example, Newman, D J, Ann Clin Biochem. 2002 March; 39(Pt2):89-104; and Perrone R D et al, Clin Chem. 1992 October;38(10):1933-53:, each of which is incorporated by reference in itsentirety. Measurement of GFR with creatinine (plasma or serumcreatinine) can be achieved with the Cockroft and Gault equation toadjust for age, weight, and gender.

An alternative measurement of GFR can be achieved with Cystatin C.Cystatin C has a low molecular weight and is filtered freely at theglomerular membrane. Cystatin C has been proposed as an alternative andsuperior marker to serum creatinine. Cystatin C is produced by allnucleated cells and catabolized by renal tubular cells. Its rate ofproduction is constant and is not affected by muscle mass, inflammation,and it does not have a circadian rhythm.

Cystatin C was found to be more specific than serum creatinine inevaluating renal function with a tighter distribution of values aroundthe regression line (Mussap, M; Kidney International, Vol 61 (2001), pp1453-1461, which is incorporated by reference in its entirety). Mussapalso reported that Cystatin C rises earlier and more rapidly than serumcreatinine as GFR decreases—it has higher sensitivity than both serumcreatinine and GFR derived from the Cockroft-Gault equation. commercialtest for serum Cystatin C is available from Dade Behring (nephelometricassay; N-latex Cystatin C Assay; 6 minute test).

Markers of Electrolyte Balance

Electrolyte balance is the condition where a patient's electrolytes (forexample, soluble ions such as Na⁺ and K⁺) are in the normalconcentration range. The subject may be a heart failure patient with astable condition, a heart failure patient with an unstable condition, apatient with mild, moderate, or advanced hypertension, or a patient withrecent myocardial infarction. Typical values of normal fluid andelectrolyte balance are as follows and are dependent upon the age andsex of the individual: for an average 70 kg man the total body water istypically 42 L (˜60% of body weight), with 28 L being in theintracellular and 14 L in the extracellular compartments. The plasmavolume is 3 L and the extravascular volume is 11 L. Total body Na⁺ istypically 4200 mmol (50% in extracellular fluid, (ECF)) and the totalbody K⁺ is typically 3500 mmol (about 50-60 mmol in ECF). The normalosmolality of ECF is 280-295 mosmol/kg.

Hypokalemia is a common adverse effect of diuretic therapy and may alsoincrease the risk of digitalis toxicity. Hence, plasma or serumpotassium levels should be routinely measured in heart failure patientsin order to avoid such undesirable side effects. Potassium is typicallymeasured using an ion-selective electrode (e.g. i-STAT, i-STAT Corp.)

Markers of Sodium Retention

Markers of sodium retention or excessive sodium intake can provide anestimate of sodium retention, electrolyte balance, and sodiumconsumption. One suitable marker is uroguanylin, which is an intestinalnatriuretic hormone and functions as an endocrine modulator of sodiumhomeostasis. In a patient with congestive heart failure, levels ofuroguanylin measured in urine are known to be substantially higher thanin controls. The increased urinary uroguanylin excretion in patientswith heart failure may be an adaptive response. The urinary excretion ofuroguanylin is significantly higher in the presence of a high salt dietand significantly correlated with urinary sodium. Measurement ofuroguanylin can provide unique information on sodium homeostasis and thepatient's status. Such measurement may be used to make decisions onintake of fluid and sodium to avoid adverse events.

Diagnostic Device

A homecare diagnostic device enables a heart failure patient and healthcare provider to safely optimize the care plan, and to track and steerthe patient's response to therapy, diet, and lifestyle. The device canmeasure and record the levels of one or more biomarkers, record patientinput regarding signs and symptoms of disease, provide feedback to thepatient, and provide recorded results to a health care provider.

Using the device, the patient's condition can be monitored remote from adedicated health care facility, such as doctor's office or hospital.Providing information to optimally manage the patient's condition helpsto prevent left ventricular volume overload. The information can alsohelp to predict the onset of acute decompensation arising through leftventricular volume overload, thereby allowing early intervention. Use ofthe device can ensure that interventions aimed at reducing fluid volumedo not over-compensate, resulting in dehydration. The device can helpthe health care provider measure the effectiveness of bothpharmacological and non-pharmacological aspects of the care plan, and tomonitor the progression of the disease. The device can also aid inassessing the patient's compliance to therapy and future prognosis.

The biomarkers measured by the device can include a marker of leftventricular volume overload or myocardial stretch, a marker ofmyocardial apoptosis or injury, a marker of myocardial ischemia, amarker of inflammation, a marker of anemia, a marker of renal function,a marker of electrolyte balance, or a marker of sodium retention. Inaddition, the device can include probes for measuring the patient'svital signs, such as weight, temperature, heart rate, variability ofheart rate, breathing rate, blood pressure, and blood oxygen saturation(measured, for example, by pulse oximetry). The device can recordelectrical measurements, such as an electrocardiogram, from the patient.The device can present queries to the patient and record the patient'sresponses. The queries can relate to the patient's condition, such aswhether the patient is suffering any symptoms or when medication wastaken.

In general, the patient will use the device on a regular basis asinstructed by a caregiver. For example, the patient may use the devicedaily, every other day, weekly, or on another appropriate interval.Under certain circumstances, fewer than all available tests will beperformed. For example, a patient may perform a blood pressuremeasurement on a daily basis, but measure a marker of left ventricularvolume overload or myocardial stretch on a weekly basis. Based on theresults of the tests, the device can respond with instructions for thepatient. The instructions can be configured based on a treatmentalgorithm. The algorithm can be adjusted to suit the needs of thepatient. For example, if a health care provider can enter informationspecific to a particular patient (such as a threshold value for abiomarker) into the device.

The biomarkers can be measured in a sample. The sample is taken from thepatient and can be a sample of blood, plasma, serum, saliva or urine. Inone embodiment, the sample is a blood sample. Such a sample may be takenby the patient by, for example, collecting a blood sample having avolume of less than one microliter up to a volume of several hundredmicroliters following puncture of the skin with an appropriate lancingdevice. The biomarkers monitored can be detected using, for example, animmunoassay, a biosensor, an ion-selective electrode, or anothersuitable technology.

For example, the markers can be detected using an immunoassay. Animmunoassay is performed by contacting a sample from a subject to betested with an appropriate antibody under conditions such thatimmunospecific binding can occur if the marker is present, and detectingor measuring the amount of any immunospecific binding by the antibody.Any suitable immunoassay can be used, including, without limitation,competitive and non-competitive immunoassay systems or ligand-bindingsystems known to one skilled in the art.

For example, a marker can be detected in a fluid sample by means of aone-step sandwich assay. A capture reagent (e.g., an anti-markerantibody) is used to capture the marker. Simultaneously, a directly orindirectly labeled detection reagent is used to detect the capturedmarker. In one embodiment, the detection reagent is an antibody. Such animmunoassay or another design known to one skilled in the art can beused to measure the level of an aforementioned biomarker in anappropriate body fluid.

A GFR marker (e.g. serum creatinine) can be measured using a biosensor,an enzymatic assay, or amperometrically. See, for example, ErlenkotterA, Anal Bioanal Chem. 2002 January; 372(2):284-92; Leger F, Eur J.Cancer. 2002 January; 38(1):52-6; and Tombach B, Clin Chim Acta. 2001October; 312(1-2):129-34, each of which is incorporated by reference inits entirety.

The measurement of a biomarker by both immunoassay and biosensor (e.g.colorimetrically) has been demonstrated by Metrika with their patentedMODM™ (Micro Optical Detection Method) technology. This integratesminiaturized digital electronics, micro-optics and solid-statechemistries into an easy to use, low-cost, single-use instrument. MODMtechnology is designed for simultaneous measurement of immunodiagnosticand general chemistries in less than ten minutes. Ostex InternationalInc. has used the same technology to develop the OSTEOMARK NTxPoint-of-Care (POC). This is a disposable single use device thatprovides a normalized measurement of the bone marker ‘NTx’ by measuringNTx and creatinine levels in a sample and then calculating the ratioresult. The POC is intended for use in a physician's office and takes 5minutes to process.

The device can be included in a diagnostic kit, which can optionallyinclude one or more of the following: instructions for using the kit forevent detection, diagnosis, prognosis, screening, therapeutic monitoringor any combination of these applications for the management of patientswith pre-heart failure, heart failure, or hypertension; a disposabletesting cartridge containing the necessary reagents to conduct a test;or an instrument or device that measures the result of biomarker testingand optionally, allows manual or automatic input of other parameters,storage of said parameters, and evaluation of said parameters alongsideor separate from the evaluation of the measured biomarkers.

The testing cartridge or cartridges supplied in the kit allow the userto measure as a minimum, a marker of left ventricular volume overload ormyocardial stretch and optionally a measurement of a marker of renalfunction, a measurement of a marker of myocardial apoptosis, ameasurement of a marker of myocardial ischemia, a measurement of amarker of myocardial injury, a measurement of a marker of anemia, ameasurement of a marker of electrolyte balance, and a marker of sodiumretention.

Preferably, the testing cartridge or testing cartridges allow thesequential or serial measurement of a marker of left ventricular volumeoverload or myocardial stretch and a marker of renal function.

The testing cartridge or testing cartridges allow the sequential orserial measurement of a marker of left ventricular volume overload ormyocardial stretch, a measurement of a marker of renal function, ameasurement of a marker of myocardial apoptosis or injury, a measurementof a marker of myocardial ischemia, a measurement of a marker ofinflammation, a measurement of a marker of anemia, a measurement of amarker of electrolyte balance, and a marker of sodium retention. Acombination cartridge can test two or more different markers from asingle sample.

The instrument (durable or disposable), at a minimum, measures theresult of biomarker testing and optionally, allows manual or automaticinput of other parameters, storage of said parameters, and evaluation ofsaid parameters with or separate to the measured biomarkers.

Referring to FIG. 1, diagnostic device 100 includes display 120 andinput region 140. The display 120 may be used to display images invarious formats, for example, joint photographic experts group (JPEG)format, tagged image file format (TIFF), graphics interchange format(GIF), or bitmap. Display 120 can also be used to display text messages,help messages, instructions, queries, test results, and variousinformation to patients. In some implementations, display 120 supportsthe hypertext markup language (HTML) format such that displayed text mayinclude hyperlinks to additional information, images, or formatted text.Display 120 can further provide a mechanism for displaying videosstored, for example in the moving picture experts group (MPEG) format,Apple's QuickTime format, or DVD format. Display 120 can additionallyinclude an audio source (e.g., a speaker) to produce audibleinstructions, sounds, music, and the like.

Input region 140 can include keys 160. In one embodiment, input region140 can be implemented as symbols displayed on the display 120, forexample when display 120 is a touch-sensitive screen. Patientinstructions and queries are presented to the patient on display 120.The patient can respond to the queries via the input region.

Device 100 also includes cartridge reader 180, which accepts diagnostictest cartridges for reading. The cartridge reader 180 measures the levelof a biomarker based on, for example, the magnitude of a color changethat occurs on a test cartridge 400. Device 100 also includes probeconnections 200, which connect probes (e.g., a probe of weight,temperature, heart rate, variability of heart rate, breathing rate,blood pressure, or blood oxygen saturation) to the device.

Device 100 further includes a communication port 220. Communication port220 can be, for example, a connection to a telephone line or computernetwork. Device 100 can communicate the results of patient tests to ahealth care provider from a remote location. Likewise, the health careprovider can communicate with the device 100 (e.g., to access storedtest results, to adjust device parameters, or send a message to thepatient).

Cartridge 400 is shown with two testing zones 420. In general, acartridge can include 1, 2, 3, 4, or 5 or more testing zones. Eachtesting zone 420 can test the level of a biomarker. Each testing zone420 includes a sample input 440, a control result window 460 and a testresult window 480. In one embodiment, the cartridge 400 is animmunochromatographic test cartridge. Examples of immunochromatographictests and test result readers can be found in, for example, U.S. Pat.Nos. 5,504,013; 5,622,871; 6,235,241; and 6,399,398, each of which isincorporated by reference in its entirety.

A patient can use device 100 for testing and recording the levels ofvarious biomarkers that provide information about the patient's health.Various implementations of diagnostic device 100 may access programsand/or data stored on a storage medium (e.g., video cassette recorder(VCR) tape or digital video disc (DVD); compact disc (CD); or floppydisk). Additionally, various implementations may access programs and/ordata accessed stored on another computer system through a communicationmedium including a direct cable connection, a computer network, awireless network, a satellite network, or the like.

The software controlling the diagnostic device and providing patientfeedback can be in the form of a software application running on anyprocessing device, such as, a general-purpose computing device, apersonal digital assistant (PDA), a special-purpose computing device, alaptop computer, a handheld computer, or a network appliance.

A diagnostic device may be implemented using a hardware configurationincluding a processor, one or more input devices, one or more outputdevices, a computer-readable medium, and a computer memory device. Theprocessor may be implemented using any computer processing device, suchas, a general-purpose microprocessor or an application-specificintegrated circuit (ASIC). The processor can be integrated withinput/output (I/O) devices to provide a mechanism to receive sensor dataand/or input data and to provide a mechanism to display or otherwiseoutput queries and results to a service technician. Input device mayinclude, for example, one or more of the following: a mouse, a keyboard,a touch-screen display, a button, a sensor, and a counter.

The display 120 may be implemented using any output technology,including a liquid crystal display (LCD), a television, a printer, and alight emitting diode (LED). The computer-readable medium provides amechanism for storing programs and data either on a fixed or removablemedium. The computer-readable medium may be implemented using aconventional computer hard drive, or other removable medium such asthose described above with reference to. Finally, the system uses acomputer memory device, such as a random access memory (RAM), to assistin operating the diagnostic device.

Implementations of a diagnostic device can include software that directsthe patient in using the device, stores the result of biomarkermeasurements, determines whether a tested biomarker level requiresmedical attention for the patient, instructs the patient in adjusting ormaintaining therapy, and communicates the patient's information to hisor her caregiver. Patients suffering from, for example, heart failure orhypertension, or patients at risk of a myocardial infarction can use thedevice.

The device 100 can provide access to applications such as a medicalrecords database or other systems used in the care of patients. In oneexample, the device connects to a medical records database viacommunication port 220. Device 100 may also have the ability to goonline, integrating existing databases and linking other websites.Online access may also provide remote, online access by patients tomedical information, and by caregivers to up-to-date test resultsreflecting the health of patients.

The device can be used in the hospital, physician's office, clinic, andpatient's home either by the patient or an attendant care giver. In oneembodiment, the invention is practiced in the patient's home allowingthe patient to be monitored, his or her therapy optimized, and adverseevents that require hospitalization to be avoided.

The device can provide information on the patient's status and provideinstructions or other actionable information to the healthcareprofessional and/or the patient. Examples, without limitation, ofinstructions that can be given include: change diuretic dose, withholddiuretic, introduce another diuretic, contact caregiver, no change incare plan necessary, change fluid intake, withhold potassiumsupplementation, and increase potassium supplementation. The objectiveis to track the patient's condition and steer him or her toward a stablecondition through appropriate interventions made by the patient or thecaregiver. Algorithms for treatment decisions are known. An example of aset of treatment algorithms can be found in: Healthcare Guideline;Congestive Heart Failure in Adults, Institute for Clinical SystemsImprovement, Release July 2003; and Silver M, Pisano C, Clanci P,Outpatient management of heart failure: Program development andexperience in clinical practice, Advocate Christ Medical Center, OakLawn, Ill., Post Graduate Institute for Medicine 2003, each of which isincorporated by reference in its entirety.

Decision Points

The device can be configured to respond to the measured level of abiomarker, in particular when the level of the biomarker indicates achange in the patient's health status. For example, the device can beconfigured to store the results of tests and determine changes in thelevels of markers over time. A change in results over time can be anacute change or a chronic change. An acute change can be a significantchange in the level of a biomarker over a short period of time. Themagnitude of change and period of time can be different for eachbiomarker. The device can be configured to compare each new test resulteither to a stored values of recent test results (e.g., the previous 1,2, 3, 4, 5 or more results), or to an aggregate measure of recent testresults (such as an average) to determine if an acute change hasoccurred. In one example, an acute change is detected by the percentagechange in a test result from the previous result.

Chronic changes can be detected as well. A chronic change can be achange in the level of a biomarker that occurs over a long period oftime. For example, a chronic change can occur such that many testingintervals pass without an acute change being detected, yet the level ofbiomarker is significantly different. To detect a chronic change, thedevice can compare the results of each new test to a stored result of anearlier test, or to an aggregate measure of earlier tests. For detectingchronic changes, the earlier test can be, for example, 4-12 weeks priorto the new test result. In one example, the aggregate measure can be arolling average, such as a 4-week, 8-week, or 12-week rolling average.

The device can also be configured to compare test results to a storedthreshold value or range. The threshold value can be an upper or lowerlimit or range of values. Thus, the device can determine if the measuredvalue of a marker, or group of markers, is a safe level, a dangerouslevel, or indicates an emergency. The device can alert the patient tothe results of the test and can be configured, when appropriate toinstruct the patient to seek medical care.

The device can also be configured to track combinations of markers, forexample, an average value of two markers, the difference in levelbetween two markers, a ratio of the levels of two markers, or whethertwo or more markers exceed their respective threshold values at the sametime. The device can be configured to track one or more markers incombination with a patient's signs and symptoms.

The device can be personalized for a patient. The threshold values andother parameters for each biomarker can be adjusted (for example, by aphysician or other caregiver) based on the circumstances of the patient,such as, for example, age, gender, or disease status. The questions andresponses that the device presents to the patient can also be adjusted.

Examples of how the device can record, detect changes, and respond todetected changes in the level of a biomarker are presented below. Thethreshold values and levels of biomarkers referred to below are notlimiting, may not be appropriate for all patients, and are for purposesof example only.

Marker of Left Ventricular Volume Overload and Myocardial Stretch

In one embodiment, the device is configured to measure the biomarker BNPin a patient sample. The device can track the patient's BNP level as afunction of time and detect changes in the BNP level. The changes can beacute or chronic. When a change in BNP level is detected, the device canrespond with a request for additional input for the patient orinstructions for the patient.

The device can determine a patient's baseline level of BNP, againstwhich future measurements of BNP will be compared. The baseline levelcan be set based on data on the influence of the patient's gender, age,body mass, and degree of hypertrophy. The baseline can also be refinedto set reasonable treatment targets for a patient taking intoconsideration the degree of disease comorbidities and the patient'sprognosis. A series of BNP measurements can be used to set a baselinefor a patient.

For example, the baseline can be defined as the average of the mostrecent two test results with an increase of maximum 10% (compared to theprevious baseline) out of the last four tests. The following testresults are excluded from the calculation:

-   -   Any test result flagged with an acute symptom    -   Any test of the 2 used for the calculation is older than 28 days    -   The last 4 tests have been done in less than 4 days

Under certain conditions, no baseline value will be available, such asthe first use of the device (i.e., no test results have been recorded);after the device has been reset; or when any of the test results usedfor the baseline calculation is older than 28 days. By testing 4 timesover at least 4 days, the initial baseline can be calculated. When thebaseline is defined in this way, the device cannot give warnings foracute deterioration over this initial 4 day period. In case one value ofthe two used for the calculation is older than 28 days, one additionaltest can be sufficient to calculate the baseline. The baseline can be avariable baseline, changing as the most recent test results change invalue.

The device can detect acute changes in BNP level, and advise the patientto take appropriate responses. Criteria for determining an appropriateresponse can include the patient's initial BNP level, which can reflectthe patient's risk profile; the percentage change in BNP level; thepresence or absence of acute symptoms; and the evolution of BNP valuesto confirm a trend and exclude assay-to-assay, physiological, andstatistical variations. When an acute increase in BNP level is detectedby the device, the device can query the patient for the presence ofacute symptoms. In advising a patient of a response to take to anincreased BNP levels, the presence of one or more acute symptoms can bea deciding factor. Acute symptoms can include chest pain (AMI); asqueezing or crushing chest feel (AMI); pain radiating to neck, left arm(AMI); sweating, nausea, or vomiting (AMI, Stroke, pulmonary TE); lossof consciousness; acute dyspnea (AMI, decompensation, pulmonarythrombo-embolism); palpitations without exercise; dyspnea when layingdown (right heart decompensation); sudden headache (stroke); and suddenvision impairment (stroke). See, for example, Harrisson T. R. et al,Principles of Internal Medicine. McGraw Hill, Inc. 1983, 1432-34 &1353-58 & 2038-39, which is incorporated by reference in its entirety.When the patient indicates that any acute symptoms are present, thedevice can advise the patient to seek medical care at once.

If there is an acute increase in BNP level, but the patient is notexperiencing any acute symptoms, the device's response can depend on thepercentage change in BNP level and the absolute BNP level. In general, alarge percentage increase in BNP level and a high absolute level canindicate a deterioration in the patient's condition, and the device canrespond by prompting the patient to seek medical care at once. A smallerpercentage change and lower absolute level may not require immediatemedical attention, and the change in BNP level can be confirmed by asecond test. In one example, the severity of a patient's disease can bestratified by absolute BNP levels as follows (see, for example, ClericoA, et al. Clin Chem Lab Med 2002 April; 40(4): 371-7; and Nomura H, etal. J Am Geriatr Soc 2002 September; 50(9): 1504-9, each of which isincorporated by reference in its entirety):

<20 pg/mL Healthy 20-50 pg/mL 1 risk factor: hypertension or age 50-100pg/mL 2 risk factors: hypertension, age, post-AMI >100 pg/mL chronichart failure patient NYHA classes 1-4

Changes in BNP level can also be grouped by severity, for example, noincrease, an increase of less than 10%, 10-20%, 20-30%, 30-40%, or 40%or more.

A second test can exclude assay-to-assay or physiological variations andthus confirm the increase. The second test can be given after apredetermined interval, which can vary depending on the severity of theincrease (e.g., within 30 minutes, 60 minutes, the same day, or within24 hours of the first test). If the second test result is a lower BNPvalue, then a third test can be performed. The third test can confirm anincrease in this case, or, for example, exclude a non-pathologicaltransient rise of more than 20% due to exercise.

For example, if the BNP level increases by 10% or less (and the patienthas no acute symptoms), the device can prompt the patient to perform asecond test. The second test can be performed the next day (for example,if the patient's BNP level is less than 50 pg/mL) or sooner, such asthirty minutes later (for example, if the patient's BNP level is 50pg/mL or greater). If the BNP level has increased by 10-20%, the devicecan prompt the patient to perform a second test, for example, withinthirty minutes of the first test. If the BNP level has increased by morethan 20%, the device can prompt the patient to seek medical care atonce. An increase of more than 30% can be regarded as the stronglyindicative for ischemia and AMI or an acute heart decompensation. See,for example, Kyriakides Z S, et al. Clin Cardiol 2000 April; 23(4):285-8; and Nakamura T, et al. J. Am. Coll. Cardiol. 2002 May 15; 39(10): 1657-63, each of which is incorporated by reference in itsentirety. If the patient's BNP level has not increased, or increased byless than 5%, the device can prompt the patient to perform a second testat a predetermined interval, such as seven days.

The device can respond to the results of the second test. If the secondtest is performed on the day after the previous test (e.g., when thepatient's BNP level is less than 50 pg/mL), the device can respond asfollows. If the second test reveals a BNP level more than 20% above thebaseline, the patient is instructed to seek medical care at once. Thepatient can be instructed to perform a third test if the second testreveals a BNP level that is between 0 and 20% higher than the baseline.The third test can be performed, for example, on the day following thesecond test. If the third test indicates that the patient's BNP level isbetween 10% and 20% higher than the baseline, the patient is instructedto seek medical care at once. However, if the third test reveals a BNPlevel between 0 and 10% higher than the baseline, the baseline can beadjusted to the average of the previous baseline and the result of thethird test. The patient is instructed to resume a regular test schedule,such as once a week.

If the second test is performed within thirty minutes of the previoustest (e.g., when the patient's BNP level is 50 pg/mL or greater), thedevice can respond as follows. When the second test result is 20% ormore above the baseline, the patient is instructed to seek medical careat once. The patient can be instructed to perform a third test if thesecond test reveals a BNP level that is between 0 and 20% higher thanthe baseline. The third test can be performed within thirty minutes ofthe second test (such as when the second test result was between 10% and20% above the baseline) or within four hours of the second test (such aswhen the second test result was between 0 and 10% above the baseline).If the third test indicates that the patient's BNP level is between 10%and 20% higher than the baseline, the is instructed to seek medical careat once. However, if the third test reveals a BNP level between 0 and10% higher than the baseline, the baseline can be adjusted to theaverage of the previous baseline and the result of the third test. Thepatient is instructed to resume a regular test schedule, such as once aweek.

Chronic Changes

The device can detect chronic changes in BNP level; in other words, slowchanges that accumulate over time to reflect a change in the patient'scondition. A chronic change can be measured, for example, by observingchanges in a rolling average of BNP values, such as a rolling 2-weekaverage. To exclude increases of an acute nature, or due to a temporaryevent (such as exercise), only those chronic increases that aremanifested for at least two weeks where the increases outnumber thedecreases can be considered as chronic increases. A chronic increase canbe small (e.g., approximately 10%) when consistent over a long time(such as one month) or can be large (for example, approximately 20%)over a relatively short term (such as two weeks). It can be important toexclude increases due to assay-to-assay variability, physiologicalrises, etc., before concluding that a chronic increase has occurred. Inorder to due so, sufficient test results have to be available.Therefore, upon suspicion of a chronic increase, patients can beinstructed to perform more tests.

A rolling average can be the average of test results performed within agiven time frame. For example, a rolling two week average can be theaverage of results recorded over the previous 15 days, a rolling 4 weekaverage can be the average of results recorded over the previous 29days, and a rolling 12 week average can be the average of resultsrecorded over the previous 85 days. When calculating a rolling average,any test result recorded with an acute symptom flag (i.e., a test resultwhere the patient was suffering an acute symptom at the time of thetest) can be excluded. Under certain circumstances, a rolling averagecannot be calculated, such as the first use of the system, following asystem reset, or when the system has not been used over the relevantlength of time (e.g., 2, 4 or 12 weeks). By testing once a week over atleast 15 days (three test results), an initial 2-week rolling averagecan be calculated. This means that the device cannot give warnings forchronic deterioration over this initial 2-week period.

When a chronic increase in BNP levels is detected, the device can querythe patient for the presence of chronic symptoms. Examples of chronicsymptoms include increasing fatigue in general (heart performancereduction); shortening of walking distance or step climbing (heartperformance reduction); aggravating chronic dyspnea (right heartdecompensation, multiple pulmonary thrombo-embolism); palpitationswithout exercise; aggravating dyspnea when laying down (decompensation);aggravating swollen feet or legs; or memory loss or paralysis orequilibrium disturbance. When the patient indicates that any chronicsymptoms are present, the device can advise the patient to seek medicalcare at once.

If there is a chronic increase in BNP level, but the patient is notexperiencing any chronic symptoms, the device's response can depend onthe percentage change in BNP level and the absolute BNP level. Ingeneral, a large percentage increase in BNP level and a high absolutelevel can indicate a deterioration in the patient's condition, and thedevice can respond by prompting the patient to seek medical care atonce. A smaller percentage change and lower absolute level may notrequire immediate medical attention, and the change in BNP level can beconfirmed by a second test. In one example, the severity of a patient'sdisease can be stratified by absolute BNP levels as follows:

<20 pg/mL Healthy 20-50 pg/mL 1 risk factor: hypertension or age 50-100pg/mL 2 risk factors: hypertension, age, post-AMI >100 pg/mL chronichart failure patient NYHA classes 1-4

Chronic changes in BNP level can also be grouped by the duration in thechange, for example, a change in the two-week rolling average, a changein a 4-week rolling average, or a change over a longer interval, such asa change in the 12-week rolling average. In each of these time periods,the changes in BNP level can be grouped by severity, such as noincrease, an increase of greater or less than 7.5%, an increase ofgreater or less than 15%, an increase of less than 10%, an increase of10-30%, an increase of 30-50%, or an increase of more than 50%.

For example, when the device detects a small, chronic increase in thetwo-week rolling average (e.g., an increase of less than 10%) in thepatient's BNP level, and the patient reports no chronic symptoms, thedevice can instruct the patient to perform a second test after apredetermined interval, such as 7 days. If there is a moderate increasein the patient's two-week rolling average BNP level (e.g., an increaseof 10-30%), the device can instruct the patient to perform a second testafter a predetermined interval, such as within 24 or 48 hours. A largeincrease (e.g., of 30-50%) and a small absolute BNP level (e.g., lessthan 50 pg/mL) can cause the device to instruct the patient to perform asecond test after a predetermined interval, such as within 24 or 48hours. When the device detects a severe increase (e.g., of more than50%) in the two-week rolling average, it can instruct the patient toseek medical care at once.

If the second test result is a BNP level higher than the previoustwo-week rolling average, the device can instruct the patient to seekmedical care at once. If, on the other hand, the second test result islower than the previous result, the device can instruct the patient toperform additional test (e.g., one test each day) until the BNP leveleither returns to its previous level, or the BNP level increases, whichwill result in a prompt to the patient to seek medical care at once. Ifthe BNP level does not return to its previous level or increase withinone week, the device can prompt the patient to seek medical care atonce.

When there is a small increase in the 4-week rolling average (e.g., anincrease of less than 15%), and the patient reports no chronic symptoms,the device can instruct the patient to perform a second test after apredetermined interval, such as 7 days. When there is a large increasein the 4-week rolling average (e.g., an increase of 15% or greater), thedevice can instruct the patient to report to his or her health careprovider.

When there is a small increase in the 12-week rolling average (e.g., anincrease of less than 7.5%), and the patient reports no chronicsymptoms, the device can instruct the patient to perform a second testafter a predetermined interval, such as 7 days. When there is a largeincrease in the 4-week rolling average (e.g., an increase of 7.5% orgreater), the device can instruct the patient to report to his or herhealth care provider.

The parameters used by the devices (i.e., the values of percentagechange in BNP level, absolute BNP level, patient messages, etc.), can bealtered. For example, a physician or other health care provider canadjust the value of acute increase in BNP level required to prompt thepatient to seek medical care to a desired value. In this way, thebehavior of the device can be tailored according to the preferences of aphysician or to the needs of a particular patient or group of patients.

Markers of Renal Function

The following uses, by example, the biomarker creatinine. The acceptedmethod for use in routine care is a measure of creatinine usingadjustment with the Cockroft and Gault equation. Creatinine can provideimportant information on volume status and should be followed inpatients during optimization of pharmacological agents (e.g. an ACEinhibitor) and ideally throughout the patient's care. Tests areperformed by the patient or the healthcare provider every day, at asuitable testing interval, or with the onset of certain signs andsymptoms. An increase in serum creatinine of 0.05 to 0.5 mg/dL is anindication for reassessment of volume status. Renal function declineswith age; many elderly patients have a glomerular filtration rate below50 mL/minute. Further, as stated, an early increase of <30% in theconcentration of creatinine is expected when a patient is administeredan ACE inhibitor. GFR monitoring using, for example, creatinine isimportant in these patients.

Further, when using BNP to guide the optimization of pharmacologicaltreatment, an estimate of GFR is essential to avoid under-hydration. An‘action level’ (e.g. a level that defines a significant reduction inrenal perfusion) for GFR will require the healthcare professional and/orthe patient to follow a predefined intervention dependent on the rate ofchange of GFR over time and the absolute level. An intervention mightinclude a change in diuretic dose, withhold the diuretic, introduceanother diuretic, change fluid intake, withhold potassiumsupplementation, increase potassium supplementation, contact thehealthcare professional, refer to the Emergency Department, etc). Asdescribed, alternative markers of GFR can be used, such as Cystatin C.

Renal function can also be used as a prognostic marker, to provideinformation on a patient's health over a long period of time. Theprognostic value of a measure of renal function (e.g., GFR as determinedby a creatinine or Cystatin C measurement) can be independent of the useof renal function to monitor hydration on a short-term basis (e.g.,during diuretic use). An average measure of renal function determinedover a period of time can be used for prognostic purposes. See, forexample, Koenig W, et al. Clin Chem. 10.1373/clinchem. 2004.041889 2004November; and Gottlieb S S, et al., J Card Fail. 2002 June; 8(3):136-41,each of which is incorporated by reference in its entirety.

Marker of Myocardial Apoptosis or Injury

Measurement of a marker of myocardial apoptosis or injury, such as atroponin, in a remote setting using frequent testing is clinicallyuseful. Tests are performed by the patient or the healthcare providerevery day, at a suitable testing interval, or with the onset of certainsigns and symptoms.

Marker of Inflammation

Measurement of a marker of inflammation in a remote setting isclinically useful. The marker of inflammation can include, for example,E-selectin, P-selectin, intracellular adhesion molecule-1, vascular celladhesion molecule-1, Nourin-1, interleukin-1β, interleukin-6,interleukin-8, interleukin-10, tumor necrosis factor-alpha, hs-CRP,neutrophils, or white blood cell count. Tests are performed by thepatient or the healthcare provider every day, at a suitable testinginterval, or with the onset of certain signs and symptoms.

Marker of Anemia

Measurement of a marker of anemia, such as hemoglobin or hematocrit, ina remote setting using frequent testing is clinically useful. Tests areperformed by the patient or the healthcare provider every day, at asuitable testing interval, or with the onset of certain signs andsymptoms.

Markers Of Myocardial Ischemia

Chronic myocardial ischemia is the leading cause of impaired myocardialcontractility and heart failure. Ischemia markers (e.g. ischemiamodified albumin, oxygen-regulated peptide, and free fatty acid) have afaster release profile than early necrosis markers (e.g. myoglobin orfatty acid binding protein (H-FABP)). Tests are performed by the patientor the healthcare provider every day, at a suitable testing interval, orwith the onset of certain signs and symptoms.

Markers Of Electrolyte Balance and Markers of Sodium Retention

Levels of electrolyte balance and sodium retention may be determined bymeasurement of the levels of sodium and potassium ion concentrations inserum. This may be conveniently done using ion selective electrodes.

Examples of Use

The diagnostic kit can be used in a remote care setting (e.g. thepatient's home, a nursing home, etc).

1. Optimization of Therapy 1.1 Normalize the Patient's Fluid BalanceUsing Diuretics.

BNP levels will fall as the patient's fluid balance is returned tonormal. If adequate diuresis cannot be achieved with a single diuretic(e.g., a loop diuretic), a second diuretic will be necessary (e.g., athiazide diuretic). Careful monitoring of renal function and electrolytebalance is necessary. BNP levels cannot be used as the sole marker ofachieving a safe fluid balance.

1.2 Introduction of an ACE Inhibitor

ACE inhibitors improve prognosis mainly through their vasodilatoryeffect. Patients are at a high risk of renal dysfunction andhypotension—this has resulted in under-dosing and under-use.

Impaired renal function can be reversed by pulling back on the diureticdose without needing to down-titrate the ACE inhibitor dose.

Monitoring renal function when up-titrating an ACE inhibitor will assurethe physician that renal function is not compromised.

Doses should be up-titrated over 1-4 weeks to reach target doses. Ifadverse events occur which cannot be overcome by reducing the diureticor holding at the current dose for longer, then alternative drugs shouldbe used (e.g., angiotensin II receptor blocker (ARB) and/orhydralazine/isosorbide dinitrates).

Effective treatment will result in a gradual fall in BNP. Measurement ofa GFR marker will identify reduced renal perfusion. Sudden increases inBNP will indicate volume overload.

1.3 Introduction of a Beta-Blocker

As stated, beta-blockers reduce the harmful effects of excessive andcontinuous increased adrenergic drive on the heart and lead toimprovements in ventricular structure and function. There is an initialand transient decrease in contractility.

However, beta-blockers also reduce heart rate and blood pressure andtherefore need careful introduction and up-titration. Up-titration of abeta-blocker should be delayed when volume overload is present.

The initial dose needs to be up-titrated every 2-4 weeks as tolerated.Patients must be monitored for hypotension, fluid retention, andbradychardia. If any of these persist, the dose should be lowered untiltolerated and then increased again, more gradually. Effective treatmentwill result in a gradual fall in BNP. Sudden increases in BNP willindicate volume overload.

2. Maintenance of Therapy

Assuming that target drug levels have been achieved, the patient wouldnormally be responsible for tracking daily weight and be asked to complywith an appropriate diet. Some patients are allowed responsibility fortheir diuretics—for example, rapid weight gain can then be offset byup-titrating the diuretic dose for a day or so. The diagnostic would beused to:

-   -   i) detect the onset of decompensation    -   ii) steer diuretics/water/salt to maintain a ‘normal fluid        balance’    -   iii) provide the patient with a ‘number’ to reinforce well-being        and promote compliance

Changes in renal function caused by the introduction of an ACE inhibitorare tolerable and, in fact, an ACE inhibitor has a beneficial effect onthe kidneys. It is agreed, however, that GFR still needs to be closelytracked to i) assess the impact of an ACE inhibitor on renal functionand ii) to track for evidence of dehydration through over-use ofdiuretics.

A patient receiving a synthetic BNP (e.g., neseritide) as part of theirtreatment can be monitored. The synthetic BNP can be administered as anacute treatment (i.e., in response to an acute event) or a chronictreatment (i.e., to treat a chronic condition). In particular, thepatient's inherent BNP production can be measured by measuring thepatient's N-BNP (the inactive, N-terminal portion of proBNP). SyntheticBNPs do not include N-BNP. N-BNP is therefore a marker of the patient'sBNP production, and is not affected by administration of a syntheticBNP.

3. Tracking Exercise Training

For some patients, exercise training improves cardiac health. However,the training regimen must be calibrated to avoid overexertion. Thedevice can track the patient's training regimen, for example byrecording the frequency and duration of exercise. The records can by thepatient as a log, for example, with date, time, and a description of theexercise, or the device can be connected to an piece of exerciseequipment such as a treadmill, and make recordings directly from thepiece of equipment.

Tracking of exercise can be done in conjunction with measurement ofactual heart function using biomarkers. For example, short- andlong-term changes in a biomarker can provide information on how well thepatient is responding to the exercise training.

The device can provide instructions or reminders to the patient toexercise, as well as query the patient with regards to signs andsymptoms during and after exercise. For example, if a patient's symptomsworsen after exercise, the device can suggest a decrease in frequency orintensity of exercise, or alert a health care provider. If the patient'shealth is improving with exercise, the device can suggest an increase infrequency or intensity of exercise. A health care provider can obtainrecords of the patient's exercise from the device.

Other embodiments are within the scope of the following claims.

1. A device for monitoring cardiac health comprising a detectorconfigured to measure, in a sample taken from a patient, a level of afirst biomarker selected from the group consisting of: a marker of leftventricular volume overload or myocardial stretch, a marker ofmyocardial apoptosis or injury, a marker of myocardial ischemia, amarker of inflammation, a marker of anemia, a marker of renal function,a marker of electrolyte balance, and a marker of sodium retention.2.-50. (canceled)